Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy, Surgery, and Radiation Therapy With or Without Dexrazoxane and Trastuzumab in Treating Women With Stage III or Stage IV Breast Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Supportive care, Treatment	Completed	18 and over	NCI	CLB-49808 NCT00016276, CALGB-49808

Special Category: CTSU trial

Objectives

1. Determine the time to locoregional recurrence, time to completion of treatment, and overall survival in women with HER-2+ stage IIIA or IIIB or regional stage IV breast cancer treated with doxorubicin and cyclophosphamide with or without dexrazoxane, followed by paclitaxel with or without trastuzumab (Herceptin), followed by surgery and radiotherapy with or without trastuzumab.
2. Determine whether addition of trastuzumab to paclitaxel therapy improves response at 24 weeks of therapy in these patients.
3. Determine whether addition of trastuzumab to paclitaxel therapy increases the rate of cardiotoxicity in these patients.
4. Determine whether addition of dexrazoxane to doxorubicin and cyclophosphamide compromises response in these patients.
5. Determine whether addition of dexrazoxane to doxorubicin and cyclophosphamide reduces the rate of cardiotoxicity in these patients.
6. Determine whether long-term trastuzumab after local therapy improves disease-free survival in these patients.
7. Determine whether long-term trastuzumab after local therapy increases the rate of cardiotoxicity in these patients.
8. Determine the occurrence of any grade 3 or higher toxicity, second malignancies, acute myelogenous leukemia, or myelodysplastic syndrome in patients treated with these regimens.
9. Determine the eventual rate of breast conservation in those patients considered candidates for breast conservation prior to neoadjuvant treatment.
10. Determine the clinical response after doxorubicin and cyclophosphamide with or without dexrazoxane and the clinical/mammographic/ultrasound response after paclitaxel with or without trastuzumab, compared to the pathologic response at definitive surgery in these patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed primary infiltrating adenocarcinoma of the breast
  • Confirmed by core needle biopsy or incisional biopsy
  • Amplification of HER-2 by FISH

    OR

  • Overexpression (3+) of HER-2 by immunohistochemistry
  • Staging criteria after complete clinical and radiographic staging:
    • T3, N1, M0

      OR

    • Any T, N2 or N3, M0

      OR

    • T4, any N, M0, including clinical or pathological inflammatory disease

      OR

    • Regional stage IV disease with supraclavicular or infraclavicular lymph nodes as only site of metastasis



• Measurable or evaluable disease



• Prior ductal carcinoma in situ of the ipsilateral breast allowed if treated with excision only without mastectomy or radiation



• Metaplastic carcinoma allowed



• Synchronous bilateral primary disease allowed (provided at least 1 cancer meets staging criteria)



• No dermal lymphatic involvement with clinical inflammatory changes



• Hormone receptor status:
  • Estrogen receptor positive or negative
  • Progesterone receptor positive or negative

Prior/Concurrent Therapy:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy
• No other concurrent chemotherapy

Endocrine therapy:

• No more than 4 weeks of prior tamoxifen for disease
• Prior tamoxifen or raloxifene for longer than 4 weeks as chemoprevention allowed
• No concurrent tamoxifen or raloxifene
• No other concurrent hormonal therapy except for steroids for adrenal failure, hormones for non-disease-related conditions (e.g., insulin for diabetes), or intermittent dexamethasone as an antiemetic

Radiotherapy:

• See Disease Characteristics
• No prior radiotherapy for index malignancy
• No prior radiotherapy to the ipsilateral breast, regional nodes, mediastinum, or heart
• Prior radiotherapy to the contralateral breast for ductal carcinoma in situ or early stage invasive breast cancer allowed provided earlier radiotherapy does not preclude optimal delivery of study radiotherapy and criterion of low risk for metastasis from first malignancy is met

Surgery:

• See Disease Characteristics
• No prior sentinel lymph node biopsy

Patient Characteristics:

Age:

• 18 and over

Sex:

• Female

Menopausal status:

• Not specified

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Granulocyte count at least 1,000/mm3
• Platelet count at least 100,000/mm3

Hepatic:

• Bilirubin no greater than upper limit of normal (ULN)
• AST no greater than 2 times ULN

Renal:

• Creatinine no greater than 1.5 times ULN

Cardiovascular:

• LVEF normal by MUGA
• No uncontrolled or severe cardiovascular disease (e.g., myocardial infarction within the past 6 months, congestive heart failure treated with medications, or uncontrolled hypertension)

Other:

• No other currently active malignancy except nonmelanoma skin cancer
• Not pregnant or nursing
• Fertile patients must use effective contraception
• Patients taking tamoxifen must use effective nonhormonal contraception during and for 2 months after study

Expected Enrollment

A total of 396 patients will be accrued for this study within 4 years.

Outline

This is a randomized, open-label, multicenter study. Patients are stratified according to stage (inflammatory vs noninflammatory inoperable stage III/ regional stage IV vs operable stage III). Patients are randomized to 1 of 8 treatment arms.

• Arm I: Patients receive dexrazoxane IV over 10-20 minutes, doxorubicin IV over 5-10 minutes, and cyclophosphamide IV over 30 minutes on days 1, 22, 43, and 64. Patients receive paclitaxel IV over 1 hour and trastuzumab (Herceptin) IV over 30-90 minutes on days 85, 92, 99, 106, 113, 120, 127, 134, 141, 148, 155, and 162. Approximately 1-2 weeks after completion of neoadjuvant chemotherapy, patients undergo breast conservation surgery, modified radical mastectomy, or mastectomy. Patients with unacceptable toxicity or locoregional disease progression may undergo surgery prior to week 24 (i.e., completion of neoadjuvant chemotherapy). Beginning 2-4 weeks after breast conservation surgery or 3-5 weeks after mastectomy, patients undergo radiotherapy daily 5 days a week for 6-8 weeks. Patients receive long-term trastuzumab IV over 30-90 minutes weekly for 40 weeks beginning on week 36 (day 254).



• Arm II: Patients receive dexrazoxane, doxorubicin, and cyclophosphamide as in arm I. Patients receive paclitaxel (without trastuzumab) as in arm I. Patients undergo surgery and radiotherapy as in arm I. Patients receive long-term trastuzumab as in arm I.



• Arm III: Patients receive dexrazoxane, doxorubicin, and cyclophosphamide as in arm I. Patients receive paclitaxel and trastuzumab as in arm I. Patients undergo surgery and radiotherapy as in arm I. Patient undergo observation only for 40 weeks after completion of radiotherapy.



• Arm IV: Patients receive dexrazoxane, doxorubicin, and cyclophosphamide as in arm I. Patients receive paclitaxel as in arm II. Patients undergo surgery and radiotherapy as in arm I. Patients undergo observation as in arm III.



• Arm V: Patients receive doxorubicin and cyclophosphamide (without dexrazoxane) as in arm I. Patients receive paclitaxel and trastuzumab as in arm I. Patients undergo surgery and radiotherapy as in arm I. Patients receive long-term trastuzumab as in arm I.



• Arm VI: Patients receive doxorubicin and cyclophosphamide as in arm V. Patients receive paclitaxel as in arm II. Patients undergo surgery and radiotherapy as in arm I. Patients receive long-term trastuzumab as in arm I.



• Arm VII: Patients receive doxorubicin and cyclophosphamide as in arm V. Patients receive paclitaxel and trastuzumab as in arm I. Patients undergo surgery and radiotherapy as in arm I. Patients undergo observation as in arm III.



• Arm VIII: Patients receive doxorubicin and cyclophosphamide as in arm V. Patients receive paclitaxel as in arm II. Patients undergo surgery and radiotherapy as in arm I. Patients undergo observation as in arm III.

Treatment continues in all arms in the absence of distant disease progression.

Beginning within 12 weeks of completion of neoadjuvant chemotherapy, hormone receptor-positive patients may receive oral tamoxifen daily for 5 years.

Patients are followed every 6 months for 5 years and then annually for 5 years.

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Mark Graham, MD, Protocol chair(Contact information may not be current)		Ph: 919-966-4431 Email: gman@med.unc.edu

Registry Information
Official Title		A 2X2X2 Factorial Randomized Phase III Trial Of Multimodality Therapy Comparing 4 Cycles Of Doxorubicin And Cyclophosphamide With Or Without Dexrazoxane (AC+/-Z) Followed By 12 Weeks Of Weekly Paclitaxel With Or Without Trastuzumab (T+/-H) Followed By Local Therapy Followed By 40 Weeks Of Weekly Trastuzumab Or None In Women With HER-2+ Stage IV Breast Cancer
Trial Start Date		2001-05-01
Registered in ClinicalTrials.gov		NCT00016276
Date Submitted to PDQ		2001-03-21
Information Last Verified		2007-08-02
NCI Grant/Contract Number		CA31946

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